The present invention relates to a medical device of a biocompatible material for use in the treatment of a gap or defect in the central nervous system.
Treatment that promotes functional regeneration across a complete spinal cord transection in man does not exist. In animal experiments (1), recovery after incomplete spinal cord lesions has been achieved in adults treated with myelin-associated protein antibodies while recovery after complete lesions has been demonstrated in neonates (2).
Various attempts have been made over the years to find a replacement for direct nerve stump to nerve stump suturing. Much research has focused on the use of channels or tubular prostheses which permit the cut ends of the nerve to be gently drawn into proximity and secured in place.
All prostheses produced so far are intended for peripheral nerves such as U.S. Pat. Nos. 3,833,002, 4,759,764, 4,870,966 and SE 457 598.
The present inventors have now found that mobility can be restored in rats having complete spinal cord gaps. The gaps have been bridged with multiple intercostal nerve grafts redirecting specific pathways from white to grey matter, and the grafted area stabilised by acidic fibroblast growth factor-containing fibrin glue and compressive wiring of posterior spinal processes: Nerve bridges were created between the peripheral nerves and the spinal cord.
It has also turned out that motility can also be resored under certain circumstances when grafting white to white and grey to grey mass if special antibodies are given to the person being treated or incorporated into inserted material connecting the gap ends of the spinal cord.
The invention relates to a medical device of a biocompatible material for use in the treatment of a gap or defect in the central nerve system comprising one or more means containing connections such as holes or channels arranged for receiving nerve growht promoting materials or substances, which device has a proximal and a distal end area comprising openings from the connections, characterized in that the device is marked and arranged for coupling nerves from the grey and white matter of the central nervous system at the proximal end to certain marked areas in the proximal end area and nerves in the grey and white matter at the distal end to certain marked areas in the distal end area.
The device may be marked and arranged for coupling nerves from the grey matter of the central nervous system at the proximal end to nerves in the grey matter at the distal end and nerves in the white matter of the central nervous system at the proximal end to nerves in the white matter at the distal end. This is especially the case when antibodies are administrated in ordr to promote the nerves to grow together.
In a preferred device according to the invention the device or the means is marked and arranged for redirecting nerves from the grey matter of the central nervous system at the proximal end to nerves in the white matter at the distal end and nerves in the white matter of the central nervous system at the proximal end to nerves in the grey matter at the distal end.
The device can be used in the treatment of complete or partial gaps or defect in the central nervous system. It may consist of one or more means comprising holes or channels arranged for receiving nerve growth promoting materials or substances, which device has a proximal and a distal end area comprising openings from the holes or channels. The openings and/or the end areas may be marked for easily coupling nerves in the grey matter of the central nervous system at the proximal end of the gap to nerves in the white matter of the central nervous system at the distal end and nerves from the white matter in the distal end to nerves in the grey matter of the proximal end.
The expressions proximal and distal refer to direction to and from the head respectively of the individual receiving the transplant.
Preferably the device redirects descending motor pathways from proximal white to distal grey matter, and ascending pathways from distal white to proximal grey matter.
The device may consist of one means that has a substantially cylindrical form comprising channels bridging openings in a first part of the area of the proximal end and openings in a second part of the area of the distal end and channels bridging openings in the second part of the area of the proximal end and openings in the first part of the area of the distal.
The end area can have any suitable form and be planar or non planar such as curved or spherical.
In another embodiment of the invention the device may comprise one or more means having a substantially flat or plate like form. Tubes of biocompatible or biodegradable material containing growth promoting material and/or Schwans cells and/or one or more peripheral nerves are threaded through the holes of the plate or plates. When using a nerve fibre or bundles of nerve fibres the tubes may not be needed.
It is preferred to use as many fine nerves as possible. In the experiment with rats described below 18 peripheral nerves were used to bridge one gap of the spinal cord. It has turned out that it is possible to use even more nerves. Therefore it is postulated that upp to 200 nerves may be used on humans, such as 25-150, preferably 50-100 nerves.
It is also possible to use a device having one or more means with substantially cylindrical form and one or more means having a substantially flat or plate like form. One means with cylindrical form can be surrounded by one or more means with plate like form.
The means may also be one or more tubes of a biocompatible material to be filled with the growth promoting substance and put in place in the spinal cord. The invention also relates to the use of such tubes. The device and means may also have other forms and can e.g. be moulded to suit the subject to be treated
When plates only are used they may be threaded with bundles of nerves or with tubes of the biocompatible material filled with the growth-promoting substance. Thus the device may also comprise one or more plates and tubing to be filled when used.
In order to facilitate the redirection of the grey and white matter, the areas of the proximal and distal ends respectively of the means are divided in a first and a second part. The first and the second areas may have any form. It is possible to simply divide the end area in two parts, that may be of the same or of different size. Preferably the first area is a central area and the second area is a peripheral area situated substantially around the central area. It is however also possible that the areas have one or more parts thereof intermingling or sticking into each other with or without connection(s) to the main part area.
Preferably the device consist of one cylindrical means having a first peripheral part and a second central part of the proximal and distal end area connected to the white and grey region respectively of both ends of the gap. Channels going from the peripheral part of one end are being redirected to end up in the central part of the other end of the cylinder and vise versa.
In order to enhance long distance regeneration it is preferable to let one or more channels or bundles of nerve fibres pass the gap and insert the end of the nerves or channels further down the spinal cord. Therefore the device or the means may have some of the channels ending at the side area and not at the distal end area. For example a nerve is introduced in the white matter of the proximal end of the gap and led through a channel that opens up in the side area of the device. It is then introduced through the white matter further down beyond the gap into the grey matter.
The means of the device may be marked. The first part of the proximal end area may be marked in the same way as the first part of the distal end area as is shown in FIGS. 1a and 1b. 
When the device comprises one cylindrical means the first (peripheral) part of both end areas can be marked in a different way from the second (central) part, e.g. white and grey to correspond to the colours of the spinal cord. Marking may not be needed when the device has a transverse end area and first and second parts of the same size as the white and grey zones of the transverse area of the spinal cord.
In another embodiment the first part of the proximal end area of a means is marked in the same way as the second part of the distal end area and the second part of the proximal end area is marked in the same way as the first part of the distal end area as is means 21 in FIG. 2. This marking may be practical when only one plate is used. It is, however, also possible to use one or more plates without marking them.
The grey matter lies in the centre of the spinal cord in the form of a thick H or a butterfly surrounded by the white matter. There will be less crossing over of bundles of nerves or of channels if the first and second areas are more or less in conformity with the pattern of white and grey matter respectively in the CNS. Moreover there will be still less crossing over if the switches between the different areas take place in the same halves or region of the cross section of the means. Thus, the switches are especially made in the same left (FIG. 4E) or right side region of the spinal cord.
The device may be marked e.g. by a vertically directed line (e.g. when the device has a plate like form) or an area (e.g. when the device has a cylindrical form) in order to make the switches from white to grey matter in substantially the same left or right part of the spinal cord as was done in the rat experiment (FIG. 4E).
When two means in the form of plates are used they may be arranged as follows. A first plate is intended to be placed near the proximal end of the gap and a second plate is to be placed near the distal end of the gap. The proximal and distal end area of the first and second plate has differently marked first and second parts e.g. a white first area and a grey second part in both plates (see FIG. 3). The openings in the first part of the distal end area of the first plate and the openings of the second part of the proximal end area of the second plate are marked with figures e.g. 1 to n. The openings in the second part of the distal end area of the first plate and the openings of the first part of the proximal end area of the second plate are marked with different figures e.g. n+1 to n+m.
The marking may be in the form of different biocompatible colouring substances or different patterns.
According to the invention it is also possible to combine redirecting white to grey mass with direct coupling white to white and grey to grey mass using special antibodies. Such a device may contain isolated areas in the first part marked in the same way as the second part and vice versa, in order not to redirect only some nerves that are coupled to the isolated areas using the antibodies.
The growth promoting material may be any pharmaceutical acceptable material or substance making the grey or white matter preferably the white matter growing. It may be a nerve growth enhancer such as for example a growth factor or active analogue, fragment or derivative thereof. One or more fibres, such as a bundle of numerous fibres or axons of a peripheral nerve and/or Schwans cells may be used. The nerves may be both monofascicular and polyfascicular. Also mixtures of the above mentioned materials and substances can be used possibly together with a glue, that does not negatively affect the growth of nerves. The material may come from the individual to be treated or from other individuals from the same or some other species.
Preferably nerves coming from the ribs such as intercostal nerves are taken out from the individual to be treated and cut into pieces. These nerve pieces or parts thereof are inserted in the holes or channels in the device. It is preferred to have as many nerves as possible as more and better functions are likely to be restored the more bridges that are created. One can use 1 to 100, preferably 9 to 75 especially 15 to 40 bundles of nerve fibres.
The holes and the channels may have any transverse cross sectional form such as round, oval or square. They are preferably general tubular with round or oval lumen. The diameter may be from 1 xcexcm to 5 mm. Preferably visible bundles of peripheral nerve fibres are inserted in the channels that have a diameter of about 0.2 mm-3 mm, especially 0.5 mm-2 mm.
The device can be delivered without any growth promoting material and be used together with e.g. peripheral nerves or Schwans cells from the individual to be transplanted. It is however also possible to deliver the device with a growth promoting material put in place possibly together with pharmaceuticals or substances preventing microbial and immunological influence on the material during transport and storage or in the patient body. The device may also contain growth factors such as bioactive neotrophic factors e.g. aFGF incorporated into the material of the device or in the holes and/or channels. The growth factor may be present in a gradient concentration that may increase in the proximal or distal direction.
Different gradients can be used for the space holding nerves coming from the white and grey matter respectively.
The device and the means may have any form. The transverse sectional area may for example be round, oval, square or rectangular. Preferably it has about the same form and area as the transverse section of the gap in the spinal cord of the individual receiving the implant. The size of the individual affects the size of the spinal cord. Further the spinal cord is thicker in the regions where the nerves to the arms and legs come out. It is also possible to treat a complete or partial gap. Taking this into account, and with regard to the fact that the means may be plate like or have the form of a cylinder, the device may be produced in different sizes. The length in the direction of the spinal cord may be about 0.2 cm to 5 cm, preferably 0.5 cm to 4 cm. The length of the device is depending on the length of each means that it is composed of. The transversal area of the device and means may vary from about 0.3 cm2 to about 4 cm2.
The invention also relates to a method for restoring a deficiency in the spinal cord on humans comprising filling a device of a biocompatible material with nerves and/or Schwans cells, possibly aslo growth promoting material and possibly also a biocompatible glue and connecting white to grey mass of the spinal cord. When special antibodies are used it is also possible to couple the nerves from white to white mass and from grey to grey mass.
It is also possible to combine the two different ways of coupling the mass of the central nerve system and couple some of the nerves to the same sort of mass (i.e. white to white and grey to grey) and some other nerves from white to grey.
The device may be composed of any biocompatible material such as, for example, polyethylene vinyl-acetate (EVA); or of biocompatible hydrogels, such as polyvinyl pyrolidone, polyethylene oxide (PEO), polyurethanes, acrylates, or mixtures thereof. Preferable acrylates include methacrylates or hydroethylmethacrylates.
Alternatively it may be composed of a bioresorbable, or bioabsorbable biocompatible polymer, such as a polyanhydride, polyester, or mixtures thereof; Poly-alpha-hydroxy acids (PGA); polylactic acid, copolymers of lactic and glycolic acids, and said polymers copolymerized with other polyesters such as epsilon-caprolactone; copolymers having a glycolic acid ester and triethylene carbonate linkages, e.g. the copolymer in the MAXON (American Cyanamid Company, Wayne N.J. 07470, U.S.A.) suture; polydioxanone; polyesters formed from diols and succinic and/or oxalic acid, isomorphic copolyoxalates and poly(alkylene) oxalates; polymers made from unsymmetrically-substituted 1.4-dioxane-2.5-diones.
One can also use silicone, connective tissue fibres such as collagen, polyglycolic acid, composite made of collagen and glycosaminoglucan (see U.S. Pat. No. 4.280,954).
The material of the device is preferably permeable to body liquids and substances in order to facilitate e.g. blood vessels to growing into the device. The material shall have qualities in order to hold and keep the nerve fibres in place. Connective tissue fibres such as collagen are suitable.
The device may be produced by using flexible tubes around which the biocompatible material is moulded. The flexible tubes are bent to change the direction of the channels from the first area of the proximal end to the second area of the distal end and vice versa to create channels changing direction from white to grey matter. The tubes are then drawn out from the device.
Devices, such as plates intended for changing the direction from white to grey outside the means or between the means, can be produced as described in WO 90/05552.
The device is preferably delivered with a thread inserted in the channels. When used, bundles of nerves are tied to the thread and drawn through the channels.
When used the device comprising nerve bundles or channels of biocompatible material containing Schwans cells and/or other nerve growth promoting material are treated with a biocompatible glue containing one or more growth factors.
The glue to be used according to the invention is preferably a fibrin glue containing 50-200 mg/ml, preferably 100 mg/ml of fibrinogen and 0.2 xcexcg-20 xcexcg per ml especially 1 xcexcg-5 xcexcg per ml, especially 2.1 xcexcg/ml of aFGF (acidic fibroblast growth factor).
The fibrin glue may be a fibrinogen based compound with double sealant components (Beringplast R P, Behring, Behringwerke A G, Margburg, Germany), containing a vial A with fibrinogen concentrate consisting of 115-232 mg dry substance, containing a human plasma protein fraction with 65-115 mg fibrinogen and a human plasma protein fraction with a factor XIII activity of 40-80 U, and a vial B with aprotinin solution consisting of 1 ml solution containing 1000 KIU bovine lung aprotinin and a vial C of thrombin consisting of 4.9-11.1 mg dry substance containing a human plasma protein fraction with a thrombin activity of 400-600 IU and a vial D with a calcium chloride solution consisting of 2.5 ml solution containing 14.7 mg calcium chloride 2H2O (40 mmol).
The advice of the supplier is followed and the aFGF is added to the vial A when used.